The adrenal gland, catecholamine synthesis

1. The Adrenal Gland The Adrenal Gland
Atif Hassan Khirelsied
, Ph.D ,
Department of Biochemistry
Faculty of Medicine
International University of Africa

2. The Adrenal Glands
•The two adrenal 
g
lands are 
g
located on the anterior 
surface above the kidne
y
s.
y
•Each gland weighs about 6 
thlftdli
grams, 
th
e 
le
ft
 a
d
rena
l is 
longer and thinner. 

3. The Adrenal Glands

4. The Adrenal Glands

5. The Adrenal Glands
ƒ
Theadrenalglandiscompoundglandcomprises
ƒ
The
 adrenal
 gland
 is
 compound
 gland
, 
comprises
 
two different endocrine tissues. 
ƒCross sectioning through the adrenal gland reveals 
a pale medulla in the centre  surrounded by a 
darker cortex.
ƒ
Each
ofthesetworegionsproducesadistinctly
Each
 of
 these
 two
 regions
 produces
 a
 distinctly
 
different group of hormones.

6. The cortex
•It is the outer part of the gland. •It consists of three concentric 
zones
ofcellsrichincholesterol
zones
 of
 cells
, 
rich
 in
 cholesterol
. 
•Each zone has a characteristic arrangement of cellsand 
containsdifferent set of enzymes, thus differ in their 
major hormonal products.

7. The adrenal cortex
•
Zona
glomerulosa
•
Zona
glomerulosa
, 
predominantly secretes 
mineralocorticoids mineralocorticoids (aldosterone). 
•Zonafasiculata,
the main 
sourceof
glucocorticoids
source
 of
 glucocorticoids
(cortisol) and androgens.
•Zonareticularis,
produces 
androgens androgens

8. The Adrenal Gland
•
Theadrenalmedulla(AM)isactuallyanextensionof The
 adrenal
 medulla
 (AM)
 is
 actually
 an
 extension
 of
 
the sympathetic NS “special ganglion”.
1. The splenic nerveterminates in the AM, innervates 
th
h ffill
th
e c
h
roma
ffi
n ce
ll
s.
2. Chromaffin cells produce the catecholamines.

9. The hormones of the adrenal medulla
•Chromaffin cells produce the catecholamines.
1. Epinephrine
2. Norepinepherine
3. Dopamine. Thilf
lif
•
Th
ey are not essent
ia
l f
or 
lif
e.
Aidf
di
(
•
A
re requ
ire
d
 f
or a
d
aptat
ion to stress 
(
acute , 
chronic).
•Major element for severe stress.

10. The biosynthesis of catecholamines

11. The biosynthesis of catecholamines
Tyrosine hydroxylase
1. Produces L‐3
,4‐dih
y
drox
yp
hen
y
lalanine 
(
L‐DOPA
)
. 
,
yypy(
)
2. Is the rate limittingenzyme. 3
Iron
‐
containingprotein[ferricstate(Fe
2
)]
3
.
Iron
‐
containing
 protein[ferric
 state(Fe
)]
.
4. Exists in soluble and particle forms.
5
Ull
5
.
U
ses mo
lecu
lar oxygen.
6. Requires tetrahydrobiopterin(BH
4
).

12. The biosynthesis of catecholamines
•Tyrosine hydroxylaseinhibitors.
1
Feedback
inhibitedbyitsproducts
1
.
Feedback
 inhibited
 by
 its
 products
.
2
Canbecompetiti elinhibitedbt rosinederi ati es
2
.
Can
 be
 competiti
v
el
y 
inhibited
 b
y 
t
y
rosine
 deri
v
ati
v
es
 
( e.g., α‐methyltyrosine), used for treatment of 
pheochromocytoma pheochromocytoma
.
3
Clbi hibit dbi
hltit(
3
.
C
an a
lso 
b
e 
in
hibit
e
d
 b
y 
iron‐c
h
e
la
ti
ng agen
t
s 
(
e.g., 
αα
‐‐bipyridine).
22
‐‐bipyridyl

13. The biosynthesis of catecholamines
•Aromatic L‐amino acid (Dopa) 
decarboxylase
ƒSynonyms
: 
–tryptophan decarboxylase, 
–5‐hydroxytryptophan decarboxylase. 
ƒIt catalyzes several different 
decarboxylation reactions:
•L‐DOPA to dopamine
•5‐HTP to serotonin
•tryptophan to tryptamine

14. The biosynthesis of catecholamines
•Aromatic L‐amino acid (Dopa) decarboxylase
1. Soluble form. 2
Req ires
pyridoxalphosphate
2
.
Req
u
ires
 pyridoxal
 phosphate
.
3. Is competitively inhibited by α‐methyl dopa.
4. Can also be inhibited by halogenated compounds.
5. Anti‐hypertension drugs (methyl dopa, 3‐
hydroxtyramine, α‐methyl tyrosine, metaramino
l) 
inhibits this enzyme .

15. The biosynthesis of catecholamines
•Dopamine‐β‐hydroxylase(DBH)
1. Converts do
p
amine to nore
p
ine
p
hrine
p
pp
2. Requires ascorbic acid as e
‐
donor.
3.
Has
Cu
inactivesite.
3.
Has
 Cu
 in
 active
 site.
 
4. Use fumarateas modulator

16. The biosynthesis of catecholamines
•
Phenylethanolamine
‐
N
‐
methyl
transferase
(PNMT)
•
Phenylethanolamine
‐
N
‐
methyl
 transferase
(PNMT)
1. Soluble in cytoplasm. 2
Id db
ltiid
2
.
I
n
d
uce
d
 b
y g
lucocor
ti
co
id
s.
3. Uses SAM, methyl donor.

17. The regulation of catecholamines synthesis
1
Stimulatedby
splanchnic
nerve
1
.
Stimulated
 by
 splanchnic
nerve
.
2. Increases after acute stress by activation of enzymes.
3
En mesareind cedbchronicstress(
corticoids
)
3
.
En
zy
mes
 are
 ind
u
ced
 b
y 
chronic
 stress
 (
corticoids
)
.

18. The storage, release and uptake of catecholamines •Storage .
1. Stored in the chromaffin granules 2. Associated with ATP‐Mg
2+
and Ca
2+
•Release .
1. By exocytosis(Ca
2+
‐dependent)
2. Stimulated by cholinergicand β‐adrenergic
3. Inhibited by α‐adrenergic •Uptake.
Neuronal uptake of the hormone is necessary for:
1. Conservation of the hormone
2. Termination of signal

19. The catecholamines receptors
•α1 .
1. Acts via calcium. 2. Increases glycogenolysis.
3. Smooth muscle contraction (blood vessels, urinogenital
tract
)
tract
)
.
•
α
2
.
α
2
.
1. Inhibits cAMPformation.
2. Smooth muscle relaxation (GIT)
3. Smooth muscle contraction (some vascular beds)
4. Inhibits:
1
li l i
1
.
li
po
lys
is
2. Reninerelease
3. Platelets aggregation
4. Insulin secretion

20. The catecholamines receptors
•β1 .
1. Stimulates cAMPformation 2. Stimulates lipolysis
3. Increases mycocardialcontraction (rate and force) •β2.
1. Stimulates cAMPformation
2. Increases smooth muscle contraction (bronchi, blood 
vesselsGITandGUT) vessels
, 
GIT
 and
 GUT)
3. Increases:
1. He
p
atic 
g
luconeo
g
enesis
p
gg
2. Hepatic glycogenolysis
3. Muscle  glycogenolysis
4. Release of insulin, glucagon and renin

21. Types of adrenergic receptors
Receptor
Effectively
EffectofLigand
Physiologic
Receptor
Effectively

Binds
Effect
of
Ligand
Binding
Physiologic

Effects
α
Norepinephrine
Increasedfree
↑v
asoconstriction
α
1
Norepinephrine
,
Epinephrine.
Increased
free

calcium
↑
v
asoconstriction
.
↑ smooth muscle
contraction.
↑
ki d i l
↑
s
ki
n an
d
v
i
scera
l

arterioles constriction.
↑ sphincters and pilomotor
α
2
Norepinephrine,
Epinephrine.
Decreased cyclic
AMP
constriction. ↓ insulin secretion

22. Types of adrenergic receptors
Receptor Effectively Effect of Ligand Physiologic
Binds Binding Effects
β
Ei hi
Idli
↑
htt
β
1
E
p
i
nep
h
r
i
ne,
Norepinephrine
I
ncrease
d
cyc
li
c
AMP
↑
h
ear
t
ra
t
e
↑ heart strength
↑ lipolysis.
Β
2
Epinephrine Increased cyclic
AMP
↑ vasodilatation.
↑ bronchodilatation.
↑
lli
↑
g
l
ycogeno
l
ys
i
s.
↑ glycolysis
↑ calorigenesis.
↑ relaxation of intestine, uterus
and bladder wall.

23. The catecholamines mechanism of signaling
•
Bindingto
β
1
and
β
2
•
Binding
 to
 β
1
 and
 β
2
 .
1. Stimulates G‐proteins coupled to adenylatecyclase.
•Binding to α2.
1. Inhibits adenylatecyclase.
•Binding to α1.
1
Iscoupledto
phospholipase
Cincreases
1
.
Is
 coupled
 to
 phospholipase
C
, 
increases
 
phosphoinsitol, DAG and Ca
2+
.

24. The catabolism of catecholamines
1. Have very short t½ (10‐30 sec) 2. Less than 5% is excreted in urine 3. Catabolizedby:
hl
hl
f
()
1. Catec
h
o
l‐o‐met
h
y
l trans
f
erase
(
COMT
)
 
2. Monoamine oxidase

25. Catecholamine degradation
COMT = Catechol‐o‐methyl transferase, MAO = Monoamine oxidase,  DOPAC
=
3
4
Dihydroxyphenylaceticacid
MHPG
=
3
Methoxy
4
hydroxyphenylglycol
DOPAC
 =
 3
,
4
‐
Dihydroxyphenylacetic
 acid
,  
MHPG
 =
 3
‐
Methoxy
‐
4
‐
hydroxyphenylglycol
 , 
DHPG= 3,4 dihydroxyphenylglycol, 
VMA= Vanillylmandelic acid,   HVA= homovanillicacid (HVA,